ASPARAGINE-RICH METASTATIC NICHES DRIVE PROSTATE CANCER ORGANOTROPISM BY ENABLING TRANSLATIONAL REWIRING TOWARD N-GLYCOSYLATED PROTEINS

ABSTRACT Metastatic disease is the leading cause of mortality in prostate cancer (PC), with bone as the preferential site of dissemination and the lung frequently affected secondarily. Metabolic interactions between disseminated tumor cells and tissue-specific microenvironments play a key role in shaping site-specific metastatic patterns. In particular, the availability of certain metabolites before, during, and after the establishment of overt metastases represents a critical determinant of colonization. Here we show that asparagine (Asn) is selectively enriched in bone and lung microenvironments and supports PC metastatic colonization. Dietary Asn restriction selectively impairs bone and lung metastases in vivo , without affecting metastatic burden in other organs. Mechanistically, disseminated PC cells arriving at Asn-rich niches rely on extracellular Asn due to decreased asparagine synthetase (ASNS) expression enabling the activation of mTORC1-dependent translational program. Elevated Asn availability selectively promotes the synthesis of Asn-rich proteins enriched in N-glycosylation motifs (Asn-X-Ser/Thr), leading to enhanced global protein N-glycosylation during early metastatic colonization. This metabolic adaptation facilitates cell-cell interactions and promotes adhesion to bone- and lung-specific extracellular matrices. Among the N-glycosylated proteins induced by Asn, CD44 emerges as a central effector of PC bone metastases. Extracellular Asn shortening, genetic or pharmacological disruption N-glycosylation, or silencing of CD44 abolish the pro-metastatic advantage conferred by Asn. Together, these findings identify environmental Asn as a niche-specific metabolic cue that drives PC organotropism by rewiring translation toward proteins enriched in N-glycosylation sites, thereby enhancing adhesive interactions and revealing metabolic vulnerabilities that could be therapeutically exploited to interfere with earliest steps of metastatic colonization in PC.